UTX condensation underlies its tumour-suppressive activity.

UTX (also known as KDM6A) encodes a histone H3K27 demethylase and is an important tumour suppressor that is frequently mutated in human cancers1. However, as the demethylase activity of UTX is often dispensable for mediating tumour suppression and developmental regulation2-8, the underlying molecular activity of UTX remains unknown. Here we show that phase separation of UTX underlies its chromatin-regulatory activity in tumour suppression. A core intrinsically disordered region (cIDR) of UTX forms phase-separated liquid condensates, and cIDR loss caused by the most frequent cancer mutation of UTX is mainly responsible for abolishing tumour suppression. Deletion, mutagenesis and replacement assays of the intrinsically disordered region demonstrate a critical role of UTX condensation in tumour suppression and embryonic stem cell differentiation. As shown by reconstitution in vitro and engineered systems in cells, UTX recruits the histone methyltransferase MLL4 (also known as KMT2D) to the same condensates and enriches the H3K4 methylation activity of MLL4. Moreover, UTX regulates genome-wide histone modifications and high-order chromatin interactions in a condensation-dependent manner. We also found that UTY, the Y chromosome homologue of UTX with weaker tumour-suppressive activity, forms condensates with reduced molecular dynamics. These studies demonstrate a crucial biological function of liquid condensates with proper material states in enabling the tumour-suppressive activity of a chromatin regulator.

Discovery and optimization of dihydropteridone derivatives as novel PLK1 and BRD4 dual inhibitor for the treatment of cancer.

In this study, we have designed, synthesized and tested three series of novel dihydropteridone derivatives possessing isoindolin-1-one or isoindoline moieties as potent inhibitors of PLK1/BRD4. Remarkably, most of the compounds showed preferable inhibitory activity against PLK1 and BRD4. Compound SC10 exhibited excellent inhibitory activity with IC50 values of 0.3 nM and 60.8 nM against PLK1 and BRD4, respectively. Meanwhile, it demonstrated significant anti-proliferative activities against three tumor-derived cell lines (MDA-MB-231 IC50 = 17.3 nM, MDA-MB-361 IC50 = 8.4 nM, and MV4-11 IC50 = 5.4 nM). Moreover, SC10 exhibited moderate rat liver microsomal stability (CLint = 21.3 µL·min-1·mg-1), acceptable pharmacokinetic profile (AUC0-t = 657 ng·h·mL-1, oral bioavailability of 21.4 %) in Sprague-Dawley rats, reduced hERG toxicity, acceptable PPB and CYP450 inhibition. Further research indicated that SC10 could induce MV4-11 cell arrest at the S phase and apoptosis in a dose-dependent manner. This investigation provided us with an initial point for developing novel anticancer agents as dual inhibitors of PLK1 and BRD4.

Design, synthesis, and biological evaluation of 2,4-diaminopyrimidine derivatives as potent Hematopoietic Progenitor Kinase 1 (HPK1) inhibitors.

HPK1 also referred to as MAP4K1, belongs to the category of mammalian STE20-like protein serine/threonine kinases. Its physiological function involves the down-regulation of T cell signals, and it is regarded as a new immune checkpoint of tumor immunology. In this study, we commenced our investigation with the hit compounds, focusing the efforts on structural optimization and SAR exploration to identify a novel class of 2,4-diaminopyrimidine HPK1 inhibitors. Notably, compound 14g exhibited a remarkable inhibitory effect on HPK1 kinase (IC50 = 0.15 nM), significantly suppressed the phosphorylation of the downstream adaptor protein SLP76 (pSLP76 IC50 = 27.92 nM), and effectively stimulated the secretion of the T cell activation marker IL-2 (EC50 = 46.64 nM). In vitro microsomal stability assay, compound 14g showed moderate stability in HLMs with T1/2 = 38.2 min and CLint = 36.4 µL·min-1·mg-1 proteins. In vivo pharmacokinetic studies, compound 14g demonstrated heightened plasma exposure (AUC0-inf = 644 ng·h·mL-1), extended half-life (T1/2 = 9.98 h), and reduced plasma clearance (CL = 52.3 mL·min-1·kg-1) compared to the reference compound after a single intravenous dose of 2 mg/kg in rats. These results indicated that compound 14g emerged as a promising inhibitor of HPK1.

Biomimetic Fibers Derived from an Equidistant Micropillar Platform Dictate Osteocyte Fate via Mechanoreception.

It is a big challenge to design a biomimetic physical microenvironment with greater similarity to in vivo tissue to observe real cell behaviors. We established a novel cell culture platform based on patterned equidistant micropillars with stiff and soft stiffnesses to mimic the changes that happened in the transition from normal to osteoporotic disease. We first demonstrated that the soft micropillar substrate decreased osteocyte synaptogenesis through synaptogyrin 1 and that this decrease was accompanied by impairment of cell mechanoperception and a decrease in cellular cytoskeletal rearrangement. We then found that the soft equidistant micropillar substrate reduced the osteocyte synaptogenesis mainly via the inactivation of Erk/MAPK signaling. We finally found that soft micropillar substrate-mediated synaptogenesis impacted the cell-to-cell communication and matrix mineralization of osteocytes. Taken together, this study provides evidence of cellular mechanical responses that are much more similar to those of real osteocytes at the bone tissue level.

Ameliorative Effects of Curcumin on Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM), a multifactorial and complicated metabolic disorder, is a growing public health problem. Numerous studies have indicated that bioactive compounds from herbal medicine have beneficial effects on T2DM prevention and treatment, owing to their numerous biological properties. Curcumin, the major curcuminoid of turmeric, is one of the most studied bioactive components of herbal supplements, and has a variety of biological activities. Clinical trials and preclinical research have recently produced compelling data to demonstrate the crucial functions of curcumin against T2DM via several routes. Accordingly, this review systematically summarizes the antidiabetic activity of curcumin, along with various mechanisms. Results showed that effectiveness of curcumin on T2DM is due to it being anti-inflammatory, anti-oxidant, antihyperglycemic, anti-apoptotic, and antihyperlipidemic, among other activities. In light of these results, curcumin may be a promising prevention/treatment choice for T2DM.

Enhancement of the Electric-Force Response of Carbon Black/Silicone Rubber Composites by Silane Coupling Agents.

Flexible strain sensors have a wide range of applications in the field of health monitoring of seismic isolation bearings. However, the nonmonotonic response with shoulder peaks limits their application in practical engineering. Here we eliminate the shoulder peak phenomenon during the resistive-strain response by adjusting the dispersion of conductive nanofillers. In this paper, carbon black (CB)/methyl vinyl silicone rubber (VMQ) composites were modified by adding a silane coupling agent (KH550). The results show that the addition of KH550 eliminates the shoulder peak phenomenon in the resistive response signal of the composites. The reason for the disappearance of the shoulder peak phenomenon was explained, and at the same time, the mechanical properties of the composites were enhanced, the percolation threshold was reduced, and they had excellent strain-sensing properties. It also exhibited excellent stability and repeatability during 18,000 cycles of loading-unloading. The resistance-strain response mechanism was explained by the tunneling effect theoretical model analysis. It was shown that the sensor has a promising application in the health monitoring of seismic isolation bearings.

Antibacterial, biocompatible, and mineralization-inducing properties of calcium silicate-based cements.

BACKGROUND: Different pulp capping materials have different origins and compositions, require different preparations, and may vary in their bioactive properties. AIM: The purpose of this study was to evaluate the antibacterial activity, biocompatibility, and mineralization-inducing potential of calcium silicate-based pulp capping materials. DESIGN: Six contemporary calcium silicate-based cements, ProRoot MTA, MTA Angelus, Biodentine, EndoSequence, NeoMTA 2, and NeoPutty, were evaluated. The antibacterial effects of these materials against Streptococcus mutans UA159 and Enterococcus faecalis ATCC 29212 were determined by the agar diffusion assay and the direct culture test. The biocompatibility and mineralization-inducing potential of these materials in preodontoblastic 17IIA11 cells were evaluated by the MTT assay and by Alizarin Red S staining, respectively. RESULTS AND CONCLUSION: In agar diffusion test, only Biodentine showed distinct antibacterial effects against S. mutans. All the tested materials, however, showed antibacterial effects against S. mutans and E. faecalis in the direct culture test, with Biodentine showing the strongest growth inhibition against both S. mutans and E. faecalis. All the tested materials showed acceptable biocompatibility and mineralization-supporting potential in our experimental conditions. In summary, ProRoot MTA, MTA Angelus, Biodentine, EndoSequence, NeoMTA 2, and NeoPutty demonstrated acceptable in vitro antimicrobial, biocompatible, and mineralization-supporting properties.

[Identification and visual analysis of ginsenosides in multi-steamed roots of Panax quinquefolium based on UPLC-Q-TOF-MS/MS and MALDI-MSI].

This study aims to investigate the component variations and spatial distribution of ginsenosides in Panax quinquefolium roots during repeated steaming and drying. Ultra performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS/MS) was employed to identify the ginsenosides in the root extract. Matrix-assisted laser desorption/ionization mass spectrometry imaging(MALDI-MSI) was employed to visualize the spatial distribution and spatiotemporal changes of prototype ginsenosides and metabolites in P. quinquefolium roots. The UPLC results showed that 90 ginsenosides were identified during the steaming process of the roots, and polar ginsenosides were converted into low polar or non-polar ginsenosides. The content of prototype ginsenosides decreased, while that of rare ginsenosides increased, which included 20(S/R)-ginsenoside Rg_3, 20(S/R)-ginsenoside Rh_2, and ginsenosides Rk_1, Rg_5, Rs_5, and Rs_4. MALDI-MSI results showed that ginsenosides were mainly distributed in the epidermis and phloem. As the steaming times increased, ginsenosides were transported to the xylem and medulla. This study provides fundamental information for revealing the changes of biological activity and pharmacological effect of P. quinquefolium roots that are caused by repeated steaming and drying and gives a reference for expanding the application scope of this herbal medicine.

Effects of Cuisine-Based Chinese Heart-Healthy Diet in Lowering Blood Pressure Among Adults in China: Multicenter, Single-Blind, Randomized, Parallel Controlled Feeding Trial.

BACKGROUND: More than one-fifth of the world's population consumes Chinese cuisines regularly, but no evidence-based healthy diets fitting the Chinese food culture are available for implementation. METHODS: A multicenter, patient- and outcome assessor-blind, randomized feeding trial was conducted among 265 participants with 130 to 159 mm Hg baseline systolic blood pressure (SBP) for 4 major Chinese cuisines (Shangdong, Huaiyang, Cantonese, Szechuan). After a 7-day run-in period on a control diet matching the usual local diets, participants were randomized to continue with the control diet or the cuisine-based Chinese heart-healthy diet for another 28 days. The primary outcome was SBP, and secondary outcomes included diastolic blood pressure and food preference score. Linear regression models were used to estimate the intervention effects and adjustments for the center. The incremental cost per 1 mm Hg reduction in SBP was also calculated. RESULTS: A total of 265 participants were randomized (135 on the Chinese heart-healthy diet and 130 on the control diet), with 52% women, mean age of 56.5±9.8 years, and mean SBP and diastolic blood pressure of 139.4±8.3 and 88.1±8.0 mm Hg, respectively, at baseline. The change in SBP and diastolic blood pressure from baseline to the end of the study in the control group was -5.0 (95% CI, -6.5 to -3.5) mm Hg and -2.8 (95% CI, -3.7 to -1.9) mm Hg, respectively. The net difference of change between the 2 groups in SBP and diastolic blood pressure were -10.0 (95% CI, -12.1 to -7.9) mm Hg and -3.8 (95% CI, -5.0 to -2.5) mm Hg, respectively. The effect size did not differ among cuisines (P for interaction=0.173). The mean food preference score was 9.5 (with 10 the best preferred) at baseline, and the net change during intervention was 0.1 (95% CI, -0.1 to 0.2; P=0.558). The incremental cost-effectiveness ratio per 1 mm Hg SBP reduction was CNY 0.4 (USD 0.06) per day. No difference in the number of adverse events was found between the 2 groups (P=0.259), and none of the adverse events was associated with the intervention. CONCLUSIONS: The Chinese heart-healthy diet is effective, palatable, and cost-effective in reducing blood pressure in Chinese adults with high blood pressure, with a clinically significant effect applicable across major Chinese cuisine cultures. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03882645.

The Mechanism Underlying the Regulation of Long Non-coding RNA MEG3 in Cerebral Ischemic Stroke.

Cerebral ischemic stroke is one of the leading causes of morbidity and mortality worldwide, and rapidly increasing annually with no more effective therapeutic measures. Thus, the novel diagnostic and prognostic biomarkers are urgent to be identified for prevention and therapy of ischemic stroke. Recently, long noncoding RNAs (lncRNAs), a major family of noncoding RNAs with more than 200 nucleotides, have been considered as new targets for modulating pathological process of ischemic stroke. In this review, we summarized that the lncRNA-maternally expressed gene 3 (MEG3) played a critical role in promotion of neuronal cell death and inhibition of angiogenesis in response to hypoxia or ischemia condition, and further described the challenge of overcrossing blood-brain barrier (BBB) and determination of optimal carrier for delivering lncRNA' drugs into the specific brain regions. In brief, MEG3 will be a potential diagnostic biomarker and drug target in treatment and therapy of ischemic stroke in the future.

Identification of raffinose family oligosaccharides in processed Rehmannia glutinosa Libosch using matrix-assisted laser desorption/ionization mass spectrometry image combined with machine learning.

RATIONALE: Currently, research on oligosaccharides primarily focuses on the physiological activity and function, with a few studies elaborating on the spatial distribution characterization and variation in the processing of Rehmannia glutinosa Libosch. Thus, imaging the spatial distributions and dynamic changes in oligosaccharides during the steaming process is significant for characterizing the metabolic networks of R. glutinosa. It will be beneficial to characterize the impact of steaming on the active ingredients and distribution patterns in different parts of the plant. METHODS: A highly sensitive matrix-assisted laser desorption/ionization mass spectrometry image (MALDI-MSI) method was used to visualize the spatial distribution of oligosaccharides in processed R. glutinosa. Furthermore, machine learning was used to distinguish the processed R. glutinosa samples obtained under different steaming conditions. RESULTS: Imaging results showed that the oligosaccharides in the fresh R. glutinosa were mainly distributed in the cortex and xylem. As steaming progressed, the tetra- and pentasaccharides were hydrolyzed and diffused gradually into the tissue section. MALDI-MS profiling combined with machine learning was used to identify the processed R. glutinosa samples accurately at different steaming intervals. Eight algorithms were used to build classification machine learning models, which were evaluated for accuracy, precision, recall, and F1 score. The linear discriminant analysis and random forest models performed the best, with prediction accuracies of 0.98 and 0.97, respectively, and thus can be considered for identifying the steaming durations of R. glutinosa. CONCLUSIONS: MALDI-MSI combined with machine learning can be used to visualize the distribution of oligosaccharides and identify the processed samples after steaming for different durations. This can enhance our understanding of the metabolic changes that occur during the steaming process of R. glutinosa; meanwhile, it is expected to provide a theoretical reference for the standardization and modernization of processing in the field of medicinal plants.

Structure-based drug design, synthesis, and biological evaluation of novel 1,3,5-triazine or pyrimidine derivatives containing benzoyl hydrazine moiety as PI3Kα selective inhibitors.

Phosphoinositide 3-kinase (PI3K) was an important cellular signal transducer, while PI3Kα was the most mutated family member in cancer. Selective PI3Kα inhibitors have become the frequent research in recent years because of their excellent curative effect and reduced side effects. Here, we described a series of PI3Kα inhibitors with 1,3,5-triazine or pyrimidine skeleton containing benzoyl hydrazine based on the pan-PI3K inhibitor ZSTK474 relying on the strategies of structure-based drug discovery (SBDD) and computer-aided drug design (CADD). Among them, compound F8 exhibited improved selective PI3Kα inhibition with an IC50 value of 0.14 nM and more significant anti-proliferative activities against three tumor-derived cell lines (PC-3 IC50 = 0.28 µM, HCT-116 IC50 = 0.57 µM, and U87-MG IC50 = 1.37 µM) than ZSTK-474. Compound F-8 induced a great decrease in mitochondrial membrane which caused cell cycle arrest at G1 phase and apoptosis in U87-MG cells in a dose-dependent manner. Furthermore, compound F8 induced significant tumor regressions in a xenograft mouse model of U87-MG cell line with no clear evidence of toxicity following intraperitoneal injection of 40 mg/kg. Compound F8 may serve as a PI3Kα-selective inhibitor and provided the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family.

Based on 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474), design, synthesis and biological evaluation of novel PI3Kα selective inhibitors.

Based on 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474), three series of novel 1,3,5-triazine or pyrimidine derivatives containing semicarbazones have been designed and synthesized to obtain new potent and selective PI3Kα inhibitors. Their inhibitory activities in vitro were evaluated against PI3Kα and three tumor-derived cell lines (U87-MG, MCF-7, and PC-3). We also tested promising compounds (A4, A6, A10, and B1) for other PI3K class I subtype (PI3Kß, PI3Kδ, and PI3Kγ) activity. The representative compound A10 exhibited an IC50 value of 0.32 nM against PI3Kα, and demonstrated extraordinary subtype selectivity. Furthermore, compound A10 obviously inhibited proliferation of MCF-7 cell lines, induced a great decrease in mitochondrial membrane potential leading to apoptosis of cancer cells, and arrested G2 phase in a dose-dependent manner. Additionally, compound A10 induced significant tumor regressions in a xenograft mouse model of U87-MG cell line without an obvious sign of toxicity upon 20 mg/kg oral administration. Compound A10 may serve as a PI3Kα-selective inhibitor and provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family.

2-Aminopyrimidine derivatives as selective dual inhibitors of JAK2 and FLT3 for the treatment of acute myeloid leukemia.

Dual inhibitors of JAK2 and FLT3 can synergistically control the development of acute myeloid leukemia (AML), and overcome secondary drug resistance of AML that is associated with FLT3 inhibition. We therefore designed and synthesized a series of 4-piperazinyl-2-aminopyrimidines as dual inhibitors of JAK2 and FLT3, and improved their selectivity for JAK2. Screening cascades revealed that compound 11r exhibited inhibitory activity with IC50 values of 2.01, 0.51, and 104.40 nM against JAK2, FLT3, and JAK3, respectively. Compound 11r achieved a high selectivity for JAK2 at a ratio of 51.94, and also showed potent antiproliferative activity in HEL (IC50 = 1.10 µM) and MV4-11 (IC50 = 9.43 nM) cell lines. In an in vitro metabolism assay, 11r exhibited moderate stability in human liver microsomes (HLMs), with a half-life time of 44.4 min, and in rat liver microsomes (RLMs), with a half-life of 143 min. In pharmacokinetic studies, compound 11r showed moderate absorption (Tmax = 5.33 h), with a peak concentration of 38.7 ng/mL and an AUC of 522 ng h/mL in rats, and an oral bioavailability of 25.2%. In addition, 11r induced MV4-11 cell apoptosis in a dose-dependent manner. These results indicate that 11r is a promising selective JAK2/FLT3 dual inhibitor.

Flavobacterium potami sp. nov., a multi-metal resistance genes harbouring bacterium isolated from shallow river silt.

Environmental pollution by heavy metals is becoming an increasing problem and has become a matter of great concern due to the adverse effects worldwide. In this study, we report a novel strain of multi-metal resistant bacteria. A Gram-stain-negative, strictly aerobic, non-motile, yellow, rod-shaped strain 17AT, was isolated from the shallow silt of Fuyang River located in Longdian town, Hengshui city, Hebei province, China. Strain 17AT grew at 20-35 °C (optimum, 30 °C), pH 5-10 (optimum, pH 7) and 0-2% (w/v) NaCl (optimum, 1%). Phylogenetic analyses of 16S rRNA gene sequences showed that strain 17AT was closely related to members of the genus Flavobacterium, and had the highest 16S rRNA gene sequence similarity with 'Flavobacterium panacis' DCY106T (97.5%), followed by Flavobacterium johnsoniae subsp. johnsoniae UW101T (97.3%), Flavobacterium cutihirudinis E89T (97.2%), Flavobacterium limi THG-AG6.4T (97.2%), Flavobacterium hibisci THG-HG1.4T (97.2%) and Flavobacterium johnsoniae subsp. aurantiacum DSM 6792T (97.1%). The genome size of strain 17AT was 5.4 Mb and the DNA G + C content was 34.0%. The average nucleotide identity, digital DNA-DNA hybridization and average amino acid identity values among strain 17AT and reference strains were in the ranges of 79.8-86.1%, 24.1-31.4% and 80.5-88.6%, respectively, lower than the threshold values for species delineation. Strain 17AT contained iso-C15:0 and C16:0 3-OH as the predominant fatty acids (≥ 10%). The main isoprenoid quinone of strain 17AT was identified as MK-6. The polar lipids consisted of phosphatidylethanolamine, three unidentified aminolipids, two unidentified aminophospholipids and six unidentified lipids. Comparative genomics analysis between strain 17AT and its reference type strains revealed that there are a number of metal-resistant genes in strain 17AT, which are located in 15 gene clusters responsible for the copper homeostasis, cobalt-zinc-cadmium resistance, copper resistance, and arsenic/antimony resistance, with the copper resistance protein NlpE being unique to 17AT. Combined data from phenotypic, phylogenetic and chemotaxonomic studies demonstrated that strain 17AT is a representative of a novel species within the genus Flavobacterium, for which the name Flavobacterium potami sp. nov. is proposed. The type strain is 17AT (= GDMCC 1.2723T = JCM 34833T).

Nasal splinting and mouth breathing training reduce emergence delirium after endoscopic sinus surgery: a randomized controlled trial.

BACKGROUND: Emergence delirium (ED) is generally occurred after anesthesia associated with increased risks of long-term adverse outcomes. Therefore, this study aimed to evaluate the efficacy of preconditioning with nasal splint and mouth-breathing training on prevention of ED after general anesthesia. METHODS: This randomized controlled trial enrolled 200 adult patients undergoing ESS. Patients were randomized to receive either nasal splinting and mouth breathing training (n = 100) or standard care (n = 100) before surgery. The primary outcome was the occurrence of ED within 30 min of extubation, assessed using the Riker Sedation-Agitation Scale. Logistic regression identified risk factors for ED. RESULTS: Totally 200 patients were randomized and 182 aged from 18 to 82 years with 59.9% of males were included in the final analysis (90 in C-group and 92 in P-group). ED occurred in 16.3% of the intervention group vs. 35.6% of controls (P = 0.004). Male sex, smoking and function endoscopic sinus surgery (FESS) were independent risk factors for ED. CONCLUSIONS: Preoperative nasal splinting and mouth breathing training significantly reduced the incidence of emergence delirium in patients undergoing endoscopic sinus surgery. TRIAL REGISTRATION: ChiCTR1900024925 ( https://www.chictr.org.cn/index.aspx ) registered on 3/8/2019.

A study of the efficacy of sacubitril/valsartan plus dapagliflozin combination treatment in pulmonary arterial hypertension due to left heart disease.

OBJECTIVE: To determine the efficacy of sacubitril/valsartan plus dapagliflozin in the treatment of patients with pulmonary arterial hypertension (PAH) due to left heart disease and to explore new treatment regimen for PAH due to left heart disease. METHODS: This study is a randomized controlled trial (RCT) study of 120 patients with PAH due to left heart disease admitted to the cardiovascular department of our hospital from Dec. 2019 to Dec. 2021. The patients were randomized 1:1 to the study group and control group. All patients were given baseline treatments targeting left heart disease and symptoms of PAH. In addition to the baseline treatments, patients in the control group were given sacubitril/valsartan tablets, while patients in the study group were given sacubitril/valsartan tablets plus dapagliflozin tablets. After 6 months of treatment, parameters including left heart function and exercise tolerance, Hemodynamics (left ventricular end systolic diameter [LVSED], left ventricular end diastolic diameter [LVEDD], left ventricular ejection fraction [LVEF], 6 min walk distance (6MWD), mean pulmonary artery pressure (mPAP) and pulmonary artery systolic pressure (PASP)), vascular endothelial function (plasma endothelin (ET) -1 and nitric oxide [NO]), heart failure markers (plasma N-terminal pro-brain natriuretic peptide (NT-proBNP)], inflammatory factors (serum C reactive protein [CRP], interleukin (IL)-6, and tumor necrosis factor (TNF)-α], and adverse drug reactions (ADRs) were assessed in both groups. RESULTS: Both groups had reduced LVESD and LVEDD, increased LVEF, and extended 6MWD after 6 months of treatment. The improvements in these parameters were significantly greater in the study group than in the control group (all P < 0.05). In addition, both the mPAP and PASP showed a decrease, and the mPAP and PASP in the study group were lower than those in the control group (p<0.05). Furthermore, both groups had decreased plasma ET-1 and NT-proBNP but increased plasma NO after 6 months of treatment. The improvements in these parameters were significantly greater in the study group than in the control group (all P < 0.05). Serum CRP, IL-6 and TNF-α levels were decreased in both groups after 6 months of treatment, and were significantly lower in the study group than in the control group (all P < 0.05). There was no significant difference in the overall incidence of ADRs between the two groups (P > 0.05). CONCLUSION: Sacubitril/valsartan plus dapagliflozin in the treatment with PAH due to left heart disease can improve left heart function of patients by improving vascular endothelial functions and alleviating inflammation, which helps to reduce the PAH process. Therefore, this combination treatment is safe and effective in PAH due to left heart disease.

Flavobacterium selenitireducens sp. nov., isolated from rhizosphere soil of ancient mulberry.

A Gram-stain-negative, non-motile, aerobic, yellow, convex, rod-shaped mesophilic bacterial strain, designated strain D33T, was isolated from rhizosphere soil of ancient mulberry in Dezhou city, Shandong province, PR China. The strain grew at 8-37 °C (optimum, 30 °C), pH 4-9 (optimum, pH 7) and growth occurred at 0.5-5.5 % (w/v) NaCl (optimally at 1 %). The results of the phylogenetic analyses of 16S rRNA gene and whole genome sequences indicated that D33T was closely related to members of the genus Flavobacterium and had the highest 16S rRNA gene sequence similarity with 'Flavobacterium agri' KACC 19300 (95.4 %), Flavobacterium ichthyis NST-5T (94.6 %), Flavobacterium ahnfeltiae KCTC 32467T (93.6 %) and Flavobacterium longum JCM 19141T (93.6 %). The genome size of D33T was 3.8 Mb and the DNA G+C content was 48.0 mol%. The average nucleotide identity (ANI), digital DNA-DNA hybridization (dDDH) and average amino acid identity (AAI) values among D33T and reference strains were lower than the threshold values for species delineation. The only respiratory quinone of D33T was menaquinone 6 (MK-6). The predominant fatty acids (>5 %) were C15:0, C16 : 0, C18 : 0, iso-C15:0, iso-C17 : 0 3-OH, anteiso-C15 : 0 and summed feature 9 . The polar lipid profile contained phosphatidylethanolamine, two unidentified aminophospholipids, three unidentified aminolipids and two unidentified lipids. Combined data from phenotypic, phylogenetic and chemotaxonomic studies indicated that D33T is a representative of a novel species of the genus Flavobacterium, for which the name Flavobacterium selenitireducens sp. nov. is proposed. The type strain is D33T (=GDMCC 1.1946T=KACC 22131T).

Synthesis and biological evaluation of new series of benzamide derivatives containing urea moiety as sEH inhibitors.

The pharmacological inhibition of soluble epoxide hydrolase (sEH) was shown to reduce inflammation and pain. Herein, we described a series of newly synthesized sEH inhibitors with the trident-shaped skeleton. Intensive structural modifications led to the identification of compound B15 as a potent sEH inhibitor with an IC50 value of 0.03 ± 0.01 nM. Furthermore, compound B15 showed satisfactory metabolic stability in human liver microsomes with a half-time of 197 min. In carrageenan-induced inflammatory pain rat model, compound B15 exhibited a better therapeutic effect compared to t-AUCB and Celecoxib, which demonstrated the proof of potential as anti-inflammatory agents for pain relief.

Discovery of benzamide derivatives containing urea moiety as soluble epoxide hydrolase inhibitors.

The elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) is efficient for the treatment of inflammatory and pain-related diseases. Herein, we reported the discovery of a series of benzamide derivatives containing urea moiety as sEH inhibitors. Intensive structural modifications led to the identification of compound A34 as a potent sEH inhibitor with good physicochemical properties. Molecular docking revealed an additional hydrogen-bonding interaction between the unique amide scaffold and Phe497, contributing to sEH inhibition potency enhancement. Compound A34 exhibited outstanding inhibitory activity against human sEH, with an IC50 value of 0.04 ± 0.01 nM and a Ki value of 0.2 ± 0.1 nM. It also showed moderate systemic drug exposure and oral bioavailability in vivo metabolism studies. In carrageenan-induced inflammatory pain rat model, compound A34 exhibited a better therapeutic effect compared to t-AUCB and Celecoxib. Metabolism studies in vivo together with an inflammatory pain evaluation suggest that A34 may be a viable lead compound for the development of highly potent sEH inhibitors.